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WO2004071510A1 - Composition pharmaceutique comprenant des immunosuppresseurs pour le traitement de la dermatophytose - Google Patents

Composition pharmaceutique comprenant des immunosuppresseurs pour le traitement de la dermatophytose Download PDF

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Publication number
WO2004071510A1
WO2004071510A1 PCT/GB2004/000502 GB2004000502W WO2004071510A1 WO 2004071510 A1 WO2004071510 A1 WO 2004071510A1 GB 2004000502 W GB2004000502 W GB 2004000502W WO 2004071510 A1 WO2004071510 A1 WO 2004071510A1
Authority
WO
WIPO (PCT)
Prior art keywords
nail
dermatophyte
immunosuppressant
composition according
infection
Prior art date
Application number
PCT/GB2004/000502
Other languages
English (en)
Inventor
Amar Lulla
Geena Malhotra
Original Assignee
Cipla Ltd
Wain, Christopher, Paul
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Ltd, Wain, Christopher, Paul filed Critical Cipla Ltd
Publication of WO2004071510A1 publication Critical patent/WO2004071510A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention is concerned with topical immunotherapy and compositions suitable for use therein.
  • Topical immunotherapy can be used to describe topical treatment with an agent having immunomodulatory properties.
  • topical formulations including agents with direct immunosuppressive actions have been tested in diseases believed to have an i munological basis, especially atopic dermatitis and psoriasis.
  • topical immunosuppressive agents have included tacrolimus and structurally related asomycin derivatives.
  • Tacrolimus is a hydrophobic macrolide immunosuppressant produced by Streptomyces tsukubaensis No. 9993.
  • Tacrolimus 17-allyl-l,14-dihydroxy-12-[2-(4- hydroxy-3-methoxycyclohexyl)- 1 -methylvinyl]-23,25-dimethoxy- 13, 19,21 ,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene-2,3,10,16-tetraone, which is also known as FK-506 or FR-900506, has the following structural formula:
  • Tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, cadmodulin and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. The effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T- cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF and TNF- alpha, all of which are involved in the early stages of T-cell activation. Tacrolimus inhibits proliferation and selective cytokine expression in antigen stimulated T cells in culture and also inhibits B cell proliferation at similar concentrations. Immunosuppression with tacrolimus in humans prevents allo graft rejection.
  • NF-AT nuclear factor of
  • tacrolimus inhibits T-lymphocyte activation, having a direct effect on T-lymphocytes so as to inhibit IL-2 transcription, which decreases responsiveness of T- lymphocytes to foreign antigens.
  • the action of tacrolimus on atopic dermatitis may be related to alteration of antigen presenting cells, suppression of IL-2 and co-stimulatory molecule expression, impairment of phenotypic and functional differentiation of epidermal Langerhans' cells and suppression of Thl and Th2 cytokine induction in lymph node cells.
  • the effect of tacrolimus on pruritis may be related to inhibition of histamine release from skin mast cells and impairment of de novo mast cell prostaglandin D2 synthesis along with diminished release of histamine from basophiles.
  • Tacrolimus is also reported as being used in the treatment of rejection in transplantation and autoimmune diseases, and is routinely used in transplantation of for example, the kidney, liver or heart.
  • Tacrolimus is available in both intravenous and oral formulation for the prevention of organ rejection after allogeneic liver or kidney transplantation.
  • Oral tacrolimus has been found to be useful in the treatment of psoriasis, but potentially serious side effects, such as nephrotoxicity and hypertension, has limited its use for dermatologic indications by this route of administration.
  • Topical formulations (ointments) have been extensively studied and reported to show positive effects in treatment of inflammatory skin diseases, such as atopic dermatitis and psoriasis.
  • Tacrolimus administered topically (as an ointment) has been reported to be safe and effective in the treatment of skin diseases. It has been further reported that in patients with atopic dermatitis, tacrolimus does not alter collagen synthesis and is not atrophogenic.
  • EP 1092429 discusses pharmaceutical compositions and methods for treating immune response associated disorders.
  • US Patent Applications 2002173516 and 2002013340 describe pharmaceutical compositions and methods for treating immune response associated diseases of the surface and anterior segment of the eye.
  • EP 1067926 and WO 99/51215 describe the use of tacrolimus as showing inhibitory activity on the production of nitric oxide.
  • an immunosuppressant such as tacrolimus
  • dermatophytosis may be useful for the treatment of dermatophytosis and related disorders.
  • Dermatophytoses are infectious diseases caused by a group of keratinophilic, parasitic fungi known as "dermatophytes". Dermatophyte infection can affect various keratinous tissues, such as the hair and stratum corneum of the skin causing areas of hair loss, scaliness and cutaneous and nail infection, including onychomycosis and various forms of tinea, epidermomycosis or epidermephytosis.
  • Nails function primarily to protect the tender fingertip and to facilitate manipulation of small items thereby.
  • Nail adornment preparations generally aim to protect and maintain the nail structure from microbial exposure that can lead to nail infection and disease.
  • Common adornment preparations available in the market for fingernails and toenails can include nail enamel, nail hardener, nail enamel remover, cuticle remover, nail white, nail bleach, nail polish dryer, nail buffering cream, nail moisturizer and other nail treatment products. Of the above preparations, nail enamel, nail hardener, nail enamel remover, cuticle remover, nail white, nail buffering cream and nail moisturizer, are more commonly used.
  • Nail enamel prevents contact of detergents with the nail, acting as a protectant. Furthermore, nail enamel can decrease nail water vapor loss from about 1.6 mg/cm 2 /h to 0.4 mg/cm 2 /h, which can enhance moisturization and flexibility. Nail hardeners are used to increase the strength of brittle nails caused by nail plate dehydration, often resulting from excessive contact with solvents, detergents and water.
  • Nail polish removers are liquids designed to strip the nail polish from the nail plate, and often include strong solvents and conditioning substances. These substances are thought to act as occlusive nail moisturizers retarding water evaporation.
  • Nail moisturizers are valuable in patients with dry, brittle, fissured and / or splitting nails.
  • the healthy nail contains about 16% water, becoming soft with saturation at 30%.
  • the water content of nail keratin is proportional to the relative humidity, being 7% at 20% relative humidity and 30% at 100% relative humidity.
  • Nail moisturizers are usually creams or lotions that contain occlusives which increase the water binding capacity of the nail plate.
  • compositions according to the present invention can include ingredients hitherto present in nail adornment compositions
  • compositions according to the present invention provide in addition to a decorative effect, also a therapeutic effect against immune disorders of keratinous tissue, such as the skin, hair and nails.
  • the present invention can provide therapeutic treatment of dermatophytosis, which as used herein denotes dermatophyte infection of keratinous tissue, such as the skin, hair and nails, including onychomycosis, various forms of tinea and also epidermomycosis or epidermephytosis.
  • At least one immunosuppressant or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, for use in the manufacture of a medicament for the treatment of dermatophytosis and related conditions.
  • a medicament as provided by the present invention is suitable for use in the treatment of dermatophyte infection of the nail.
  • An immunosuppressant suitable for use according to the present invention is preferably selected from the group consisting of tacrolimus, cyclosporin, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
  • the present invention also provides a method for the treatment or prophylaxis of dermatophytosis and related conditions in a patient suffering from, or susceptible to, dermatophytosis and related conditions, which method comprises topically administering to a dermatophyte infected area of keratinous tissue, or an area of keratinous tissue susceptible to dermatophyte infection, a therapeutically effective amount of at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
  • an immunosuppressant or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, can be topically administered to a dermatophyte infected area of keratinous tissue, or an area of keratinous tissue susceptible to dermatophyte infection, and as such exert a therapeutic effect thereto.
  • the treatment regime will be dependent on the patient, and severity of the dermatophyte infection being treated, and will generally be at the discretion of an attendant physician.
  • a method of the present invention is particularly suitable for topical administration of at least one immunosuppressant substantially as hereinbefore described to a dermatophyte infected area of the nail.
  • the topical administration is such that the applied immunosuppressant can substantially arrest dermatophyte invasion of, or growth on, susceptible nail tissue.
  • an immunosuppressant suitable for use according to the present mvention is included in a composition which can persist on the dermatophyte infected nail tissue after repeated washing.
  • a method according to the present invention can also have prophylactic use, and in accordance with this aspect of treatment according to the present invention an immunosuppressant can be applied to a healthy nail, particularly if adjacent nails exhibit dermatophyte infection.
  • an immunosuppressant to an area of nail tissue exhibiting dermatophyte infection, or susceptible to dermatophyte infection can be by application to the nail in a variety of ways, for example by painting the nail, through use of a dropper, and the like.
  • the immunosuppressant is applied in the form of a nail lacquer composition that can be applied as a plurality of layers onto the nail plate, typically in 2 to 3 coats.
  • An immunosuppressant suitable for use in a method according to the present invention is preferably selected from the group consisting of tacrolimus, cyclosporin, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
  • physiologically functional derivative denotes a chemical derivative of an immunosuppressant as described herein having the same or similar physiological function as the free base immunosuppressant and, for example, being convertible in the body thereto.
  • keratinous tissue as used herein denotes keratin containing tissue, including the skin, hair and nails.
  • compositions formulated for topical application to an area of keratinous tissue, such as the skin, hair or nails, exhibiting dermatophyte infection, or susceptible to dermatophyte infection, which composition comprises at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with at least one carrier therefor, wherein said immunosuppressant is included in said composition in a therapeutically effective amount so as to be capable of exerting a therapeutic or prophylactic effect respectively to an area of keratinous tissue exhibiting dermatophyte infection, or susceptible to dermatophyte infection.
  • a composition according to the present invention can be provided as a liquid, spray or gel, band aid or a cream, and in a preferred embodiment a composition according to the present invention is formulated as a lacquer for application to the nail of a patient.
  • a pharmaceutical composition formulated for topical application to an area of nail tissue exhibiting dermatophyte infection, or susceptible to dermatophyte infection which comprises at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with at least one carrier therefor, wherein said immunosuppressant is included in said composition in a therapeutically effective amount so as to be capable of exerting a therapeutic or prophylactic effect to an area of nail tissue exhibiting dermatophyte infection, or susceptible to dermatophyte infection, and further characterised in that the composition is provided as a nail lacquer.
  • An immunosuppressant suitable for use in a composition according to the present invention is preferably selected from the group consisting of tacrolimus, cyclosporin, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
  • the immunosuppressant is present in a composition according to the present invention, in particular a nail lacquer composition according to the present invention, in the range of about 0.1 to 5% of the total composition.
  • An acceptable carrier for use in a composition according to the present invention is any solvent system which can solubilise an immunosuppressant substantially as hereinbefore described and can be tolerated by human tissue.
  • suitable solvents include ethyl acetate, methyl acetate, ethanol, isopropanol, propyl acetate, n-butanol, xylene, DI acetone alcohol, aromatics (containing phenyl groups), amyl acetate, ethers, ketones, alkanes for example pentane, cyclopentane, hexane, toluene, heptane, cyclohexane, cyclic ethers for example, tetrahydrofuran and 1,4-dioxane, cellosolve, butyl cellosolve acetate, cellosolve acetate, methyl cellosolve acetate, butyl cellosolv
  • a preferred nail lacquer composition for use according to the present invention typically further comprises one or more of the following ingredients: a thixotropic compound, a suspending agent, plasticizers, secondary pigments or colorants, one or more film forming resins, UN light absorbers, stabilizers, fragrances, moisturizers, leveling agents, drying agents and the like.
  • Film formers and resins (or thixotropic compounds) suitably employed in nail lacquer compositions according to the present invention can produce a film that adheres well to the nail plate and is oxygen permeable, thus allowing gas exchange between the atmosphere and the nail plate.
  • Suitable film forming compounds can include cellulose acetate, cellulose acetate butyrate, ethyl cellulose, vinyl polymers, nitrocellulose, methacrylate and acrylate type polymers, and co-polymers and mixtures thereof.
  • Copolymers of the type obtainable by copolymerization of methylvinyl ether and either maleic acid or maleic anhydride (available under the trade mark Gantrez), and acrylate type polymers are preferred for use according to the present invention.
  • Plasticizers suitably employed in nail lacquer compositions according to the present invention may include tricresyl phosphate, dibutyl tartrate, benzyl benzoate, tributyl phosphate, butyl acetyl ricinoleate, butyl glycolate, butyl stearate, triphenyl phosphate, triethyl citrate, camphor, castor oil, esters of citric, stearate, phalic, oleic, phosphate, butyric and benzoic acid, glyceryl triacetate and glyceryl tripropionate, 2,2,4-trimethyl-l,3- pentandiiol diisobutyrate and mixtures thereof.
  • a nail lacquer composition according to the present invention may include the use of phthalate type plasticizers either alone or in combination with the aforementioned plasticizers, for example diamylphthalate, dibutyl phthalate, diethyl phthalate, dioctyl phthalate, dibutoxy ethylphthalate and mixtures thereof.
  • secondary pigments and / or organic colorants can be added to the compositions to provide cosmetically acceptable shades.
  • Pigments and / or organic colorants for use in the present invention may include any of those pigments or organic colorants which are generally known for use in nail enamel compositions.
  • compositions according to the present invention may include cosmetic grade or purified titanium dioxide, yellow and red iron oxides, aluminium platelets, iron blue, iron black, mica particles, ultramarine blue, D&C red #7, chromide oxide greens, carbon black, lampblack and the like.
  • Other pigments that may be used in compositions according to the present invention may include lake pigments, for example D&C red #6 barium lake, D&C red #7 calcium lake and the like.
  • a suspending agent may also be used in nail lacquer compositions according to the present invention and these can include colloidal clays, montmorillonite clays, especially stearalkonium hectorite, stearalkonium bentonite, fumed silica and mixtures thereof.
  • a nail lacquer composition according to the present invention may also include additional additives including stabilizers, UN light absorbers such as ectocrylene and benzophenone, fragrances, moisturizers and the like.
  • the present invention also provides a process of preparing a composition as described herein, which process comprises providing at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, in the form of a composition suitable for topical administration to an area of keratinous tissue, such as the skin, hair or nails, of a patient substantially as hereinbefore described.
  • Tacrolimus was dissolved in 50% ethanol. Gantrez was also dissolved in ethanol. The solutions were mixed, ethyl acetate added and the volume made up with ethanol.
  • Tacrolimus was dissolved in 50% ethanol.
  • Eudragit El 00 was dissolved in ethanol. The solutions were mixed, butyl acetate and methylene chloride were added to the resulting solution and the volume made up with ethanol.
  • Tacrolimus was dissolved in 50% ethanol.
  • Plastoid B was dissolved in ethanol. The solutions were mixed, butyl acetate and methylene chloride were added to the resulting solution and the volume made up with ethanol.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

La présente invention a trait à l'utilisation d'au moins un immunosuppresseur, ou un sel, solvate pharmaceutiquement acceptable ou un dérivé physiologiquement fonctionnel de celui-ci, dans le traitement de la dermatophytose et des conditions associées, et à des compositions pour une telle application.
PCT/GB2004/000502 2003-02-11 2004-02-11 Composition pharmaceutique comprenant des immunosuppresseurs pour le traitement de la dermatophytose WO2004071510A1 (fr)

Applications Claiming Priority (2)

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IN179MU2003 2003-02-11
IN179/MUM/2003 2003-02-11

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WO2004071510A1 true WO2004071510A1 (fr) 2004-08-26

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1767247A1 (fr) * 2005-09-26 2007-03-28 Faber-Castell AG Composition cosmétique liquide pour la coloration des ongles et de la peau
JP2010132607A (ja) * 2008-12-05 2010-06-17 Taisho Pharm Ind Ltd アトピー性皮膚炎治療用軟膏剤
JP2010202546A (ja) * 2009-03-02 2010-09-16 Taisho Pharm Ind Ltd アトピー性皮膚炎の治療用軟膏製剤
EP2345414A4 (fr) * 2008-10-08 2012-02-22 Takata Seiyaku Co Ltd Préparation de tacrolimus pour applications externes
EP2127677A4 (fr) * 2006-12-27 2012-05-02 Astellas Pharma Inc Copolymère de méthacrylate d'aminoalkyle e pour maintenir la solubilité d'un médicament médiocrement soluble dans l'eau
US20220241250A1 (en) * 2018-07-26 2022-08-04 Maruho Co., Ltd. Liquid topical preparation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0321128A1 (fr) * 1987-12-14 1989-06-21 Efamol Holdings Plc Compositions d'acide gras
WO2000037071A1 (fr) * 1998-12-21 2000-06-29 Aps Kbus 8 Nr. 4788 Traitement local de dermatoses
WO2001041780A2 (fr) * 1999-12-13 2001-06-14 Fujisawa Pharmaceutical Co., Ltd. Nouvelle utilisation
WO2001060345A2 (fr) * 2000-02-18 2001-08-23 Novartis Ag Composition pharmaceutique
US20020013340A1 (en) * 2000-02-18 2002-01-31 Peyman Gholam A. Treatment of ocular disease

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0321128A1 (fr) * 1987-12-14 1989-06-21 Efamol Holdings Plc Compositions d'acide gras
WO2000037071A1 (fr) * 1998-12-21 2000-06-29 Aps Kbus 8 Nr. 4788 Traitement local de dermatoses
WO2001041780A2 (fr) * 1999-12-13 2001-06-14 Fujisawa Pharmaceutical Co., Ltd. Nouvelle utilisation
WO2001060345A2 (fr) * 2000-02-18 2001-08-23 Novartis Ag Composition pharmaceutique
US20020013340A1 (en) * 2000-02-18 2002-01-31 Peyman Gholam A. Treatment of ocular disease

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1767247A1 (fr) * 2005-09-26 2007-03-28 Faber-Castell AG Composition cosmétique liquide pour la coloration des ongles et de la peau
EP2127677A4 (fr) * 2006-12-27 2012-05-02 Astellas Pharma Inc Copolymère de méthacrylate d'aminoalkyle e pour maintenir la solubilité d'un médicament médiocrement soluble dans l'eau
EP2345414A4 (fr) * 2008-10-08 2012-02-22 Takata Seiyaku Co Ltd Préparation de tacrolimus pour applications externes
JP2012149097A (ja) * 2008-10-08 2012-08-09 Takada Seiyaku Kk タクロリムス外用剤
JP5135441B2 (ja) * 2008-10-08 2013-02-06 高田製薬株式会社 タクロリムス外用剤
US8575189B2 (en) 2008-10-08 2013-11-05 Takata Seiyaku Co., Ltd. Tacrolimus preparation for external applications
JP2010132607A (ja) * 2008-12-05 2010-06-17 Taisho Pharm Ind Ltd アトピー性皮膚炎治療用軟膏剤
JP2010202546A (ja) * 2009-03-02 2010-09-16 Taisho Pharm Ind Ltd アトピー性皮膚炎の治療用軟膏製剤
US20220241250A1 (en) * 2018-07-26 2022-08-04 Maruho Co., Ltd. Liquid topical preparation

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